1. Field of the Invention
This invention relates generally to proliferative disorders such as cancer and, more specifically, to PR/SET-domain containing genes and gene products that can be used to diagnose and treat proliferative disorders.
2. Background Information
Cancer is one of the leading causes of death in industrialized nations. Cancerous tumors result when a cell escapes from its normal growth regulatory mechanisms and proliferates in an uncontrolled fashion. Cells from the primary tumor generally metastasize to vital organs if treatment of the primary tumor is either not complete or not initiated early enough. Thus, early diagnosis and effective treatment of tumors is essential for survival.
Cancer involves the clonal replication of populations of cells that have gained competitive advantage over normal cells through the alteration of regulatory genes. Regulatory genes can be broadly classified into “oncogenes” which, when activated or overexpressed promote unregulated cell proliferation, and “tumor suppressor genes” which, when inactivated or underexpressed fail to prevent abnormal cell proliferation. Loss of function or inactivation of tumor suppressor genes is thought to play a central role in the initiation and progression of a significant number of human cancers.
A number of tumor suppressor genes have been identified that, when inactivated, are involved in the initiation or progression of human cancers. Known tumor suppressor genes include RB, p53, DCC, APC/MCC, RIZ, NF1, NF2, WT1, VHL, BRCA1, MST1 and WAF1/CIP1. Approaches for treating cancer by modulating the function of several of these tumor suppressor genes, either with pharmaceutical compounds that target their encoded proteins, or by gene therapy methods, have yielded promising results in animal models and in human clinical trials.
Approaches for diagnosing and prognosing cancer by identifying mutations in tumor suppressor genes have also been developed. For example, identifying individuals containing germline mutations in known tumor suppressor genes has permitted the identification of individuals at increased risk of developing cancer. Such individuals are then closely monitored or treated prophylactically to improve their chance of survival. Identifying the pattern of alterations of known tumor suppressor genes in biopsy samples is also being used to determine the presence or stage of a tumor. Being able to determine whether a cancer is benign or malignant, or at an early or late stage of progression, provides the patient and clinician with a more accurate prognosis and can be used to determine and monitor the course of treatment.
One important family of tumor suppressor genes that has recently been identified are PR/SET−domain containing genes. PR and SET domains are structurally related motifs present in proteins that function in modulating gene activities from yeast to mammals. A PR domain is a motif first identified as a region of homology between the Rb-binding zinc finger protein RIZ, and the transcriptional repressor protein PRDI-BF1/Blimp1, which promotes B-cell differentiation (Buyse et al., Proc. Natl. Acad. Sci. USA 92:4467-4471 (1995); Huang, Cell 78:9 (1994)). A PR domain motif is also found in the MDS1-EVI1 myeloid leukemia gene (Fears et al., Proc. Natl. Acad. Sci. USA 93:1642-1647 (1996)). A SET domain is a motif first identified as a region of homology between the Drosophila melanogaster genes Su(var)3-9, Enhancer-of-zeste and Trithorax. PR and SET domain-encoding genes have also been identified in other mammals and in lower organisms, including C. elegans, suggesting an evolutionarily conserved function for these domains.
In view of the importance of tumor suppressor genes and related molecules in the detection and treatment of cancer, there exists a need to identify additional tumor suppressor genes. In particular, in view of the established role of PR/SET-domain containing genes as tumor suppressor genes, there exists a need to identify and characterize additional PR/SET-domain family members. The present invention satisfies this need and provides related advantages as well.